Rett syndrome (RTT) is an X-linked disorder caused by MECP2 mutations and is the only autism- spectrum disorder with a known genetic cause. MeCP2 is developmentally regulated in both human and mouse. MECP2 mutations or expression defects are found not only in RTT but are also observed in a subset of autism-spectrum cases. Therefore understanding the role of MeCP2 in brain development is relevant to the study of RTT and other autism-spectrum disorders. Defects in higher cortical function are clearly associated with RTT and autism. However, hindbrain dysgenesis may also play a role. Genes which are involved in the process of hindbrain development include Homeobox genes of the Hox family and EGR2. Hoxa1 and EGR2 interact syngergistically in a dosage- dependent manner to partition portions of the rhombencephalon. EGR2 is also expressed throughout the later prenatal and postnatal periods in areas of the brain including the brainstem and cerebellar neurons and may be involved in synaptic plasticity. Both EGR2 and Hoxa1 are identified as potential MeCP2 targets by gene expression profiling. The aim of this proposal is to investigate whether dysregulation of EGR2 or Hoxal contributes to the phenotype of RTT or other autism spectrum disorders. Using techniques including immunohistochemistry, RNA FISH and laser scanning cytometry, the hindbrain of the MeCp2-null mouse will be examined for abnormalities in structure and gene expression. Chromatin immunoprecipitation will be utilized to examine whether EGR2, Hoxa1 and MeCP2 interact to program early hindbrain development. Expression of EGR2 and Hoxal will also be examined in human postmortum RTT and autism brain. Elucidating gene expression networks for MeCP2 targets and MECP2 regulators may aid in the earlier diagnosis and treatment of RTT and autism. Lay summary: Rett syndrome (RTT) is caused by MECP2 mutations and is the only autism-spectrum disorder with a known genetic cause. MeCP2 expression may also be implicated in other autism-spectrum disorders. The aim of this proposal is to investigate whether EGR2 and Hoxa1 are part of a regulatory gene network which impacts the RTT and autism phenotypes. Elucidating gene expression networks for MeCP2 targets and MeCP2 regulators may aid in the earlier diagnosis and treatment of this devastating class of neurodevelopmental disorders. [unreadable] [unreadable]